Investigator s Brochure

Transcription

1 Investigator s Brochure SPONSOR PRODUCT Multidisciplinary Association for Psychedelic Studies (MAPS) 3,4-methylenedioxymethamphetamine (MDMA) IND # DATA CUT-OFF DATE 01 October 2015 EFFECTIVE DATE 30 March 2016 EDITION 8 th Edition REPLACES 7 th Edition (dated 01 August 2013)

2 Table of Contents List of Figures and Tables... 4 List of Abbreviations Summary Introduction Physical, Chemical, and Pharmaceutical Properties and Formulation Nonclinical Studies Nonclinical Pharmacology Pharmacology in Animals Pharmacokinetics in Animals Pharmacodynamics in Animals Stable Effects on Gene Expression in Animals Immunological Effects in Animals Thermoregulatory Effects in Animals Cardiovascular Effects in Animals Osmoregulatory Effects in Animals Neurobiological Effects in Animals Neuropsychological Effects in Animals Physiological Effects in Epidemiological Settings Immunological Effects Thermoregulatory Effects Cardiovascular Effects Osmoregulatory Effects Neurobiological Effects Neuropsychological Effects Toxicology in Animals and Epidemiological Settings Single Dose Studies in Animals Repeated Dose Studies in Animals Genotoxicity Carcinogenicity Reproductive and Developmental Toxicity Hyperthermia Cardiovascular Toxicity Hyponatremia Hepatotoxicity Neurotoxicity Serious Reports, Mortality, and Morbidity in Animals and Epidemiological Settings Abuse Potential in Nonclinical Studies Effects in Humans in Clinical Settings History of Use in Clinical Settings Pharmacology in Humans Pharmacokinetics Pharmacodynamics Safety of MDMA in Humans Reproductive and Developmental Immunological Effects Thermoregulatory Effects Cardiovascular Effects Osmoregulatory Effects Page 2 of 143

3 5.3.6 Hepatic Effects Neurobiological Effects Neuropsychological Effects Cognitive Function Perceptual Effects Social Effects Emotional Effects Suicidal Ideation, Behavior, and Depression Adverse Events Commonly Reported Adverse Events Adverse Events Serious Adverse Events Abuse Potential Efficacy of MDMA Across Populations PTSD Social Anxiety in Autistic Adults Anxiety Associated with Life-Threatening Illness Summary of Data and Guidance for the Investigator Pharmacology Toxicology Physiological Effects Immunological Effects Hepatic Effects Suicidal Ideation, Behavior, and Depression Adverse Events Risk Mitigation in MDMA-Assisted Clinical Trials Abuse Potential Conclusion References Appendix Page 3 of 143

4 List of Figures and Tables Table 1: Pharmacokinetic Constants for Plasma MDMA After Various Routes of Administration to Humans or Animals Table 2: Summary of Published Morbidity and Mortality Reports Figure 1: Metabolism of MDMA in Humans Table 3: Pre-Drug, Peak, and Final Body Temperature During Experimental Sessions with Placebo or any MDMA Dose in MAPS-Sponsored Studies Across Populations Table 4: Pre-drug, Peak, and Final Systolic Blood Pressure During Experimental Sessions with Placebo or any MDMA Dose in MAPS-Sponsored Studies Across Populations Table 5: Pre-drug, Peak, and Final Systolic Blood Pressure During Experimental Sessions in Controlled Hypertension Subjects in MAPS-Sponsored PTSD Study MP Table 6: Pre-drug, Peak, and Final Diastolic Blood Pressure During Experimental Sessions with Placebo or any MDMA Dose in MAPS-Sponsored Studies Across Populations Table 7: Pre-drug, Peak, and Final Diastolic Blood Pressure During Experimental Sessions in Controlled Hypertension Subjects in MAPS-Sponsored PTSD Study MP Table 8: Pre-drug, Peak, and Final Heart Rate During Experimental Sessions with Placebo or any MDMA Dose in MAPS-Sponsored Studies Across Populations Table 9: List of All Clinically Significant Changes in Laboratory Values in Two Subjects from MP Table 10: Average ALT Values at Baseline and 2-Month Follow-up After Two Experimental Sessions in Subjects from MP Table 11: Neurocognitive Function - RBANS Mean Total Scores at Baseline, Primary Endpoint, End of Stage 1, and End of Stage 2 for MP-1, MP-4, and MP-12 as of 01 October Table 12: Neurocognitive Function - PASAT Trial 1 and Trial 2 Mean Raw Total Scores at Baseline, Primary Endpoint, End of Stage 1, and End of Stage 2 for MP-1, MP-4, and MP-12 as of 01 October Table 13: Summary of Baseline Positive and Serious Responses on C-SSRS for Studies MP-4, MP-8, MP-9, MP-12, MAA-1, and MDA-1 as of 01 October Table 14: C-SSRS Positive and Serious Responses During Experimental Sessions and 1-Day Post-Drug for Studies MP-4, MP-8, MP-9, and MP-12 as of 01 October Table 15: C-SSRS Positive and Serious Responses During Experimental Sessions and 1-Day Post-Drug for Studies MAA-1 and MDA-1 as of 01 October Table 16: C-SSRS Positive Responses During Telephone Contact Following Experimental Sessions for Studies MP-4, MP-8, MP-9, MP-12, MAA-1, and MDA-1 as of 01 October Table 17: C-SSRS Positive Responses at Endpoints After Treatment for Studies MP-4, MP-8, MP-9, MP-12, MAA-1, and MDA-1 as of 01 October Table 18: Mean BDI-II Scores at Baseline, Primary Endpoint, and End of Stage 1 by Dose for Studies MP-4, MP-8, MP-9, and MP-12 as of 01 October Table 19: Mean BDI-II Scores at Secondary Endpoint, End of Stage 2, and 12-month Follow-up for Studies MP-4, MP-8, MP-9, and MP-12 as of 01 October Table 20: Mean BDI-II Scores After MDMA or Placebo in MAA-1 as of 01 October Table 21: Mean Percentage of Subjects Reporting Commonly Reported Reactions During MDMA or Placebo Treatment Collected from 12 Phase 1 Studies Conducted Outside of Sponsor Support Table 22: Percentage of Observations of Most Commonly Reported Spontaneously Reported Reactions During Experimental Sessions in Studies MP-1, MP-2, MP-4, MP-8, MP-9, MP-12, MDA-1, MAA-1, and MP1-E2 as of 01 October Table 23: Percentage of Observations of Most Commonly Reported Spontaneously Reported Reactions During Telephone Contact on Day 1-7 After Experimental Sessions in Page 4 of 143

5 Studies MP-1, MP-2, MP-4, MP-8, MP-9, MP-12, MDA-1, MAA-1, and MP1-E2 as of 01 October Table 24: Overview of All Adverse Events Post-Drug by Severity and Relationship in MAPS- Sponsored Studies Across Populations as of 01 October Table 25: Body Systems of All Adverse Events Post-Drug Reported by 2% or More of Subjects in MAPS-Sponsored Studies Across Populations Table 26: Related Adverse Events in Sponsor Supported Studies of MDMA-Assisted Psychotherapy Across Populations Organized by Body System as of 01 October Table 27: Severe Related Adverse Events in Sponsor Supported Studies of MDMA-Assisted Psychotherapy Across Populations as of 01 October Table 28: Serious Adverse Events in Sponsor-Supported Studies of MDMA-Assisted Psychotherapy Across Populations as of 01 October Table 29: Mean Global CAPS Scores in Stage 1 of Sponsor-Supported Studies of MDMA- Assisted Psychotherapy for PTSD as of 01 October Table 30: Mean Global CAPS Scores in Stage 2 and Long-term Follow-up of Sponsor-Supported Studies of MDMA-Assisted Psychotherapy for PTSD as of 01 October Table 31: Percentage of Observations of Spontaneously Reported Reactions During Experimental Sessions in Studies MP-1, MP-2, MP-4, MP-8, MP-9, MP-12, MDA-1, MAA-1, and MP1-E2 as of 01 October Table 32: Spontaneously Reported Reactions on Day 1-7 After All Experimental Sessions in Studies MP-1, MP-2, MP-4, MP-8, MP-9, MP-12, MDA-1, MAA-1, and MP1-E2 as of 01 October Page 5 of 143

6 List of Abbreviations Ach AE(s) ALT API ARF AVP BDI BDI-II BDNF BOLD C CAPS CBF cgmp CNS COMT CPK CRA C-SSRS CTproAVP DAT DEA DBP DIC DMF DNA DSM-IV E EEG EKG ESR FDA fmri G-CSF GD HHMA HMA HMMA HPA HR IB IL IND LD50 LSD MAA-1 MAO MAO-A MAOI Acetylcholine Adverse Event(s) Alanine Aminotransferase Active Pharmaceutical Ingredient Acute Renal Failure Arginine Vasopressin Beck Depression Inventory Beck Depression Inventory II Brain Derived Neurotrophic Factor Blood Oxygen Level Dependent Celsius Clinician Administered PTSD Scale Cerebral Blood Flow Current Good Manufacturing Practice Central Nervous System Catechol-O-methyltransferase Creatine Phosphokinase Clinical Research Associate Columbia Suicide Severity Rating Scale Stimulating Secretion of Copeptin Dopamine Transporters Drug Enforcement Administration Diastolic Blood Pressure Disseminated Intravascular Coagulation Drug Master File Deoxyribonucleic Acid Diagnostic and Statistical Manual of Mental Disorders IV Embryonic Days Electroencephalography Electrocardiogram Erythrocyte Sedimentation Rate Food and Drug Administration Functional Magnetic Resonance Imaging Granulocyte-colony Stimulating Factor Gestational Days 3,4-Dihydroxymethamphetamine 4-Hydroxy-3-methoxy-amphetamine 4-Hydroxy-3-methoxy-methamphetamine Hypothalamus-pituitary-adrenal Heart Rate Investigator s Brochure Interleukin Investigational New Drug Lethal Dose in 50% of Cases d-lysergic Acid Diethylamide Phase 2 clinical trial of MDMA-assisted therapy for social anxiety in people on the autism spectrum Monoamine Oxidase Monoamine Oxidase A Monoamine Oxidase Inhibitor Page 6 of 143

7 MAPS Multidisciplinary Association for Psychedelic Studies MDA 3,4-Methylenedioxyamphetamine MDA-1 Phase 2 clinical trial of MDMA-assisted psychotherapy for anxiety in relation to a life-threatening illness MDE Methylenedioxyethylamphetamine MDMA 3,4-Methylenedioxymethamphetamine MP-1 Phase 2 clinical trial of MDMA-assisted psychotherapy for PTSD in Charleston, South Carolina MP1-E2 Relapse study Phase 2 clinical trial of MDMA-assisted psychotherapy for PTSD in Charleston, South Carolina MP-2 Phase 2 clinical trial of MDMA-assisted psychotherapy for PTSD in Switzerland MP-3 Phase 2 clinical trial of MDMA-assisted psychotherapy for PTSD in Israel MP-4 Phase 2 clinical trial of MDMA-assisted psychotherapy for PTSD in Canada MP-8 Phase 2 clinical trial of MDMA-assisted psychotherapy for PTSD in Canada MP-9 Phase 2 clinical trial of MDMA-assisted psychotherapy for PTSD in Canada MP-12 Phase 2 clinical trial of MDMA-assisted psychotherapy for PTSD in Canada MRI Magnetic Resonance Imaging mrna Messenger Ribonucleic Acid MT-1 Phase 1 clinical trial of MDMA-assisted psychotherapy for PTSD in healthy volunteers in Charleston, South Carolina NET Norepinephrine Transporter NK Natural Killer NLP Natural Language Processing PASAT Paced Auditory Serial Addition Task PET Positron Emission Tomography PFC Prefrontal Cortex PMA Paramethoxyamphetamine PMMA Paramethoxymethamphetamine PND Postnatal Day PTSD Posttraumatic Stress Disorder RBANS Repeatable Battery for the Assessment of Neuropsychological Status rcbf Regional Cerebral Blood Flow SAE(s) Serious Adverse Event(s) SBP Systolic Blood Pressure SERT Serotonin Transporter SIADH Syndrome of Inappropriate Antidiuretic-hormone Secretion SNRI Selective Serotonin and Norepinephrine Uptake Inhibitor SPECT Single Photon Emission Tomography SSRI Selective Serotonin Reuptake Inhibitor SUD Subjective Units of Distress TNF- Tumor Necrosis Factor-alpha VHD Valvular Heart Disease VMAT2 Vesicular Monoamine Transporter 2 WBC White Blood Cell Count 8-OH-DPAT 8-Hydroxy-2-(di-n-propylamino)tetralin Page 7 of 143

8 1.0 Summary The Multidisciplinary Association for Psychedelic Studies (MAPS) is a U.S.-based non-profit research and educational organization supporting research of the therapeutic potential of 3,4- methylenedioxymethamphetamine (MDMA). MAPS is sponsoring clinical trials of MDMAassisted psychotherapy for patients with chronic disorders such as Posttraumatic Stress Disorder (PTSD), social anxiety associated with autism, and anxiety related to terminal illnesses. MDMAassisted psychotherapy is an experimental treatment that combines psychotherapeutic techniques with administration of MDMA, a pharmacological adjunct that enhances aspects of psychotherapy. Prior to placement on the Drug Enforcement Administration s (DEA) list of Schedule I substances, MDMA was administered to thousands of people in psychotherapeutic practice outside of clinical trials. According to the 2011 United Nations World Drug Report, 11 to 28 million people aged 15 to 64 used Ecstasy, material represented as containing MDMA, around the world in various non-medical settings [1-5, 631]. The information presented in this Investigator s Brochure (IB) is summarized from published research studies of MDMA conducted by groups outside of the sponsor, sponsor collected data and published studies of Ecstasy use. For the purposes of this document MDMA will be used to refer to drug of known purity used in a controlled setting and Ecstasy will be used to describe drug-related information gathered from epidemiological settings. MDMA is a ring-substituted phenethylamine also known as methylenedioxymethamphetamine. MDMA is structurally similar, but functionally distinct, from amphetamines. MDMA is a chiral molecule, the sponsor uses racemic MDMA in the form of white crystalline powder compounded with inert material into capsules. The hydrochloride salt of MDMA is readily water soluble and once ionized is lipophilic. A substantial amount of data, both clinical and nonclinical, has been collected for over half a century of research on the physiological and psychological effects of MDMA in humans and animals. Estimates from animal data suggest a median lethal dose (LD50) in humans between 10 to 20 mg/kg [632]. Due to a wide range of responses to identical milligram per kilogram (mg/kg) dosing [7], the sponsor s human trials use fixed doses equivalent to between 1 and 4 mg/kg (active doses in studies range from 75 mg to 225 mg). Onset of MDMA effects occurs 30 to 60 minutes after oral administration [7, 8, 9], peak effects appear 75 to 120 minutes post-drug [10, 11, 12], and duration of effects lasts from 3 to 6 hours [10, 12, 13], with most effects returning to baseline or near-baseline levels 6 hours after drug administration. The elimination half-life of active doses is 8 to 9 hours [14]. The pharmacokinetics of MDMA in humans has been characterized using oral doses of up to 150 mg MDMA. MDMA disposition in the body follows nonlinear pharmacokinetics. As described in Figure 1 (see Section Pharmacokinetics), metabolism of MDMA results in N-demethylation to 3,4-methylenedioxyamphetamine (MDA). The parent compound and MDA are further O- demethylenated to 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), respectively. Both HHMA and HHA are subsequently O-methylated mainly to 4- hydroxy-3-methoxy-methamphetamine (HMMA) and 4-hydroxy-3-methoxy-amphetamine (HMA). These four metabolites, particularly HMMA and HMA, are known to be excreted in the urine as conjugated glucuronide or sulfate metabolites [14]. MDMA is a triple monoamine reuptake inhibitor, and similar drugs in this class have been found to exert potent anti-depressant activity with a favorable safety profile in clinical trials [15, 16]. MDMA concomitantly promotes release, inhibits reuptake, and extends duration of serotonin, norepinephrine, and dopamine in the synaptic cleft to increase serotonergic, noradrenergic, and dopaminergic neurotransmission. MDMA has self-limiting subjective and physiological effects due to inhibitory activity on tryptophan hydroxylase [17-19], which prevents additional serotonin from being produced and released. This inhibition is reversible [20]. MDMA produces anxiolytic Page 8 of 143

9 and prosocial effects through release of the monoaminergic neurotransmitters, with the greatest effect on serotonin, followed by norepinephrine and dopamine [21-25]. MDMA has been shown to acutely decrease activity in the left amygdala and increase blood flow to the prefrontal cortex (PFC) in the brain [26-28]. MDMA has also been found to increase serum levels of the neurohormones oxytocin and arginine vasopressin (AVP) in humans [19, 29-33]. Some studies in healthy volunteers suggest that MDMA increases trust and attenuates reactivity to threatening cues, which are at least partially associated with oxytocin release [29, 34, 35]. The combined neurobiological effects of MDMA can increase compassion for self and others, reduce defenses and fear of emotional injury, and make unpleasant memories less disturbing while enhancing communication and capacity for introspection [36-39]. These factors taken together can provide the opportunity for a corrective emotional experience in the context of psychotherapy. Many of the therapeutic effects of MDMA-assisted psychotherapy are evident within a short period of treatment, often after the initial session. Increased feelings of interpersonal closeness, changes in social perception and reduced anxiety may make MDMA a suitable pharmacological adjunct to enhance psychotherapy for anxiety disorders, such as PTSD and social anxiety in autistic adults [40]. MDMA may provide a muchneeded option in the treatment of PTSD and anxiety associated with other conditions. Published results from MAPS study (MP-1) showed clinically and statistically significant improvements in PTSD severity in 20 per protocol subjects [41]. Findings from the long-term follow-up of MP-1 suggest that therapeutic benefits were sustained for an average of 41 months post-treatment [42]. The sponsor s second Phase 2 pilot study conducted in Switzerland (MP-2) demonstrated clinically significant improvements in PTSD symptoms, with results in the 125 mg MDMA dose group numerically but not statistically superior to the 25 mg MDMA dose group [43]. Long-term follow-up data 12 months later suggest that therapeutic benefits continued to increase in this subject population. There were no drug-related Serious Adverse Events (SAEs) or safety concerns in either study. Data from MAPS studies and published literature show that MDMA produces sympathomimetic effects that include significant transient, self-limiting increases in heart rate (HR) and blood pressure that are likely to be well tolerated by healthy individuals [7, 9, 10, 12, 26, 44-46]. Most people do not experience elevations that exceed those seen after moderate exercise. These results were reproduced in MAPS Phase 1 safety study [47]. Risks posed by elevated blood pressure are addressed by excluding candidates with a history of cardiovascular, cerebrovascular disease, or with pre-existing uncontrolled hypertension and by regularly monitoring blood pressure and pulse throughout experimental sessions. Common reactions reported in the literature and clinical trials from MDMA are transient and diminish as drug effects wane during the session and over the next one to 7 days. The effects include lack of appetite, insomnia, dizziness, tight jaw or bruxism, difficulty concentrating, headache, impaired gait or balance, muscle tension, ruminations, feeling cold, and thirst (see Section Adverse Events). MDMA is also a mild immunosuppressant [48]. Due to their limited duration, these sub-acute reactions are not likely to have clinical significance. As of 01 October 2015, with 1180 individuals exposed to MDMA in controlled research settings (which includes 122 in MAPS-sponsored studies), there have been no unexpected drug-related SAEs to date, and expected SAEs have been rare and non-life threatening. As of the data cut-off, a single expected related SAE (increased ventricular extrasystoles), and 10 unrelated SAEs after drug administration have been reported in MAPS-sponsored clinical trials. There have been a number of SAEs reported in individuals who use Ecstasy (material represented as containing MDMA, as defined above) around the world in various non-medical settings [1-5]. These include fatalities reported after Ecstasy and poly-drug use in unsupervised and uncontrolled Page 9 of 143

10 settings. These events are relatively rare given the prevalence of Ecstasy use, estimated to be in the millions worldwide [49, 50]. The most common adverse effects in Ecstasy and poly-drug use include hyperthermia, psychiatric problems, hepatotoxicity, and hyponatremia [51-55] (see Section 4.4 Toxicology in Animals and Epidemiological Settings and 4.5 Serious Reports, Mortality, and Morbidity in Animals and Epidemiological Settings). 2.0 Introduction MDMA is not a novel compound. The history of its use in humans predates controlled studies in healthy volunteers and clinical trials. MDMA was first synthesized and patented by Merck in 1912 [56] and is currently not covered by a patent. MAPS holds the Drug Master File (DMF) and an Investigational New Drug (IND) for MDMA with the U.S. Food and Drug Administration (FDA). After MDMA was rediscovered by the chemist Alexander Shulgin in 1976 [57], he and his colleagues provided initial reports of its pharmacology, with 80 mg to 160 mg MDMA required to produce desired subjective effects in humans [58, 59]. MDMA was found to robustly influence human emotional status in a unique way [59] without adversely effecting physiological functions or perception, such as visual perception or cognition [8, 11, 13]. MDMA possesses a complex pharmacological profile that is dominated by its effects as a monoamine releaser and reuptake inhibitor, with additional effects on limiting neurotransmitter production and degradation. Its prominent effects on serotonin differentiate it from amphetamine and methamphetamine, which primarily act to increase catecholamines such as norepinephrine and dopamine [21, 60]. In the Merck Index, MDMA resides in the Entactogen class [61]. Entactogens contain a ring-substituted amphetamine core, belong to the phenethylamine class of psychoactive drugs, and are described as promoting acceptance and compassion for self and others, changing recognition and response to emotions, and increased interpersonal closeness [19, 37, 62, 63]. In comparison to anxiolytics, antidepressants and atypical antipsychotics, MDMA does not require steady state levels in the blood to function as a catalyst to psychotherapy. Two to six administrations of MDMA, spaced approximately 1 month apart at active doses of 75 mg to 125 mg, may be an alternative to other medications that require daily dosing. This infrequent dosing regimen mitigates adverse event (AE) frequency and improves the risk/benefit ratio of MDMA, which may provide a significant advantage over daily dose medications. Shulgin and Nichols were the first to report the effects of MDMA in humans [59]. MDMAassisted psychotherapy first occurred during the mid-to-late 1970s after Shulgin introduced MDMA to a psychotherapist, Leo Zeff. Reported effects of MDMA include enhanced feelings of closeness to others, wellbeing, and insightfulness [64-66]. Prior to placement in Schedule I, MDMA was used in psychotherapy for individuals, couples, and groups to treat diverse psychological disorders, including moderate depression and anxiety [65, 67-69]. It was also found to be useful in reducing physical pain secondary to certain kinds of cancer [68]. No formal controlled clinical trials of safety and efficacy were conducted at the time [65, 70]. During the early 1980s, increasing numbers of people began using MDMA, sold as Ecstasy outside of therapeutic contexts [1]. The first wave of non-medical use occurred not only in dance clubs, but also in groups of people who used the drug in a self-exploratory or spiritual context. Non-medical use continues today in the same contexts [4, 71]. In the U.S., an estimated 800,000 people reported initiating Ecstasy use in the past year [72], and approximately 2.1 million Europeans between the ages of 15 and 64, or approximately 0.6% of the population, reported using Ecstasy in 2013 [73]. Page 10 of 143

11 MDMA was added to the list of Schedule I controlled substances in the U.S. in 1985, defining it as a drug with a high potential for abuse and no accepted medical use [74, 75]. Classification as a Schedule I controlled substance, combined with the early research in animals and recreational users, hampered clinical research into the medical uses of MDMA until the 1990s. Shortly after it was scheduled, animal studies described long-term decreases in markers of serotonergic functioning after high or repeated doses of MDMA administration [76], however these were not relevant to doses in clinical trials [77, 78]. A recently published meta-analysis took careful steps to overcome methodological limitations in previous work, and found only modest indicators of long-term impairment in cognitive function in humans [53]. A systematic review of brain imaging studies in moderate ecstasy users found no convincing evidence for structural or functional changes [79]. Reports of AEs, such as hyperthermia, following Ecstasy use [80-82] and studies in Ecstasy users reporting changes in serotonin transporter (SERT) density, impaired memory and executive function raised concerns regarding the safety of MDMA administration [83-87]. However uncontrolled studies of Ecstasy use and preclinical animal studies that use inappropriately high doses of MDMA produce findings that are open to several interpretations [78, 88]. The vast majority of publications of Ecstasy users are retrospective reports in polydrugusers [53, 89]. While the initial studies in the 1990s conducted in humans examined the physiological effects of MDMA strictly from a safety perspective, current investigations have examined the effects on attention, prosocial effects, memory and brain activity, and human drug discrimination. Findings from an initial sponsor-funded study indicated that MDMA-assisted psychotherapy could be conducted safely in people with chronic PTSD who had failed first line treatments [90, 527]. This was repeated in a chronic, treatment-resistant PTSD sample in a sponsor-supported study (MP-1) [42] which demonstrated durable improvement in PTSD severity, with no difference in cognitive function between placebo and MDMA groups after an active dose of MDMA was given on two occasions, 1 month apart. In addition, placebo-controlled Phase 1 clinical trials confirmed that MDMA produces an easily controlled intoxication characterized by euphoria, increased wellbeing, sociability, self-confidence, extroversion, transient increases in anxiety, and minor alterations in perception [8, 10-12, 29, 30, 35, 91, 92]. MAPS is completing Phase 2 investigations of MDMA-assisted psychotherapy. Significant durable improvement in PTSD symptoms lasted for at least 12 months after MDMA-assisted psychotherapy in two completed studies (MP-1, MP-2) [42, 43]. There are four Phase 2 studies for treatment of PTSD that have completed treatments and are in follow-up: two studies in the U.S. (MP-8, MP-12), one in Canada (MP-4), and one in Israel (MP-9). Data from Phase 2 studies will be submitted to FDA for an End-of-Phase 2 meeting to support an application for Phase 3 multi-site MDMA/PTSD research studies. Based on the current state of scientific knowledge and the risk/benefit profile of active doses of MDMA, it appears favorable to continue the research of MDMA as an adjunct to psychotherapy. Based on clinical experience with PTSD, MAPS is exploring new indications for this treatment. Studies for additional indications include one Phase 2 study (MAA-1) of MDMA-assisted therapy for social anxiety in people on the autism spectrum and one study of MDMA-assisted psychotherapy to address anxiety associated with a life-threatening illness (MDA-1). In addition, there is one ongoing Phase 1 study of MDMA-assisted psychotherapy to assess psychological effects in healthy volunteers (MT-1). When completed, this will be the first Phase 1 investigation to assess acute effects in a therapeutic setting that is comparable to MDMA-assisted psychotherapy studies for PTSD. This IB will present preclinical and clinical studies of MDMA, as well as epidemiological studies in Ecstasy users. Page 11 of 143

12 3.0 Physical, Chemical, and Pharmaceutical Properties and Formulation MDMA is structurally similar, but functionally distinct, from amphetamines and mescaline. MDMA, also known as 3,4-methylenedioxy-N-methylamphetamine and N-methyl-3,4- methylenedioxyamphetamine, has the chemical formula of C 11H 15NO 2. It was first synthesized as a precursor of a haemostatic drug called methylhydrastinine as a phenylisopropylamine derivative of safrole, an aromatic oil found in sassafras, nutmeg, and other plants [56]. MDMA is a chiral molecule, possessing two enantiomers, S(+)-MDMA and R(-)-MDMA, with S(+)-MDMA being more potent than R(-)-MDMA [6, 58]. Research in humans to date and the majority of nonclinical studies have used racemic MDMA, or an admixture containing equal amounts of both enantiomers. Studies of drug discrimination in rodents [94, 95] and studies of self-administered and experimenter-administered MDMA enantiomers in primates [23, 96-99] suggest that MDMA enantiomers may produce different physiological and rewarding effects, and there may be some synergy between the two when administered as a racemate. It seems that R(-)- MDMA may have hallucinogen-like effects, compared to S(+)-MDMA, which exhibits psychomotor stimulant-like effects. Findings comparing the effects of the enantiomers of the related compound methylenedioxyethylamphetamine (MDE) suggest that these different effects of MDMA enantiomers may occur in humans [100]. According to an in vivo microdialysis study in rodents, S(+)-MDMA may be associated with greater dopamine release in specific brain areas [101]. A study conducted in 2014 in monkeys found that S(+)-MDMA, but not R(-)-MDMA, significantly increased extracellular dopamine levels in the dorsal striatum, whereas S(+)-MDMA significantly increased serotonin levels [23]. In vitro studies reported greater binding at a specific alpha nicotinic acetylcholine (Ach) receptor by R-MDMA compared with S-MDMA [102]. MDMA available for humans in clinical trials is racemic, containing roughly equal amounts of both enantiomers. Any differential effects of the enantiomers remain untested in humans. The sponsor will use racemic MDMA in all current and planned studies. Unless otherwise stated, MDMA is used throughout this document to refer to the racemic mixture. For clinical trials, the sponsor used racemic hydrochloride salt of MDMA from two sources. Since this is the formulation used in all prior investigations in humans, the sponsor will continue to use the hydrochloride salt of MDMA. The hydrochloride salt of MDMA is readily water soluble with a pk a of 9.9 [103], which influences whether it is ionized in plasma and slightly reduces its ability to cross into oral fluid. MDMA is also more lipophilic, which drives it into oral fluid, and may influence its ability to pass the blood brain barrier and influence signaling in the central nervous system (CNS) [104]. Sponsor-supported studies in the U.S. use MDMA manufactured in 1985 by David Nichols, Ph.D., at the Department of Medicinal Chemistry and Pharmacology, Purdue University, West Lafayette, IN. The MDMA was manufactured as a single lot for use in federally approved clinical research. A stability analysis conducted in 2006 indicates that the compound remains highly stable and pure after 21 years of storage [105]. Studies conducted outside of the U.S. use MDMA from a single batch manufactured in 1998 by Lipomed AG in Arlesheim, Switzerland. The most recent analysis of drug stability and purity conducted on February 2, 2010 confirmed that this MDMA is 99.9% pure with no detectable decomposition. For sponsor-supported studies, MDMA in the form of white crystalline powder is compounded with inert material into capsules. Capsules are administered orally with a glass of water. The sponsor has contracted with Shasun, a manufacturer in the United Kingdom, to manufacture active pharmaceutical ingredients (APIs) to produce 1 kg of MDMA following current Good Page 12 of 143

13 Manufacturing Practices (cgmp). The material is planned for use in all Phase 3 studies. Details of manufacturing are available from the manufacturer upon request. MDMA doses in sponsor-supported studies are fixed within a therapeutic dose range, rather than based on body weight, based on epidemiological information and lack of linear dose response with behavioral effects in Phase 1 and sponsor-supported studies [7]. A typical active dose is 125 mg, which is equivalent to 2 mg/kg for the initial dose. The optional supplemental dose of 62.5 mg is equivalent to 1 mg/kg, for a cumulative dose of 3 mg/kg. Various comparator and active doses of MDMA are also being tested in the clinical trials. MDMA does not require special conditions for storage. The capsules are stored in sealable containers placed within a dark safe at ambient temperature. MDMA is a Schedule I compound and is stored and handled in compliance with relevant federal and state regulations. In accordance with the requirements of the U.S. DEA and international drug regulatory authorities, license holders will be responsible for storing and dispensing the MDMA, and ensuring it is stored under appropriate protections, often in a floor-mounted safe. Lactose is used as inactive placebo and as an inactive filler intended to maintain blinding by creating capsules of equal weight. Lactose has been in use as an inactive material of similar appearance and was selected because it can be safely consumed by most people and is inactive. Whenever conducting blinded studies, the sponsor will continue to employ lactose or inactive materials that exist as white powders without significant odor that can be safely administered in humans. The purpose of this excipient is solely to permit placebo or active placebo administration under blinded conditions. 4.0 Nonclinical Studies Findings from nonclinical animal research, retrospective studies of Ecstasy use and case reports of Ecstasy use in humans are presented. Research into the pharmacological, physiological, or psychological effects of MDMA began in the 1950s, when the U.S. Army administered MDMA to guinea pigs, monkeys, mice, rats, and dogs as part of a military research program, possibly intending to develop chemical incapacitants or means of enhancing interrogation [106]. Investigations of the pharmacology, functional effects, and toxicity of MDMA in animals have generally included injections of large and often repeated doses of MDMA that are not humanequivalent doses. Studies of MDMA have been conducted in primates and rodents. Primate species studied include baboon, macaque, rhesus monkey, and squirrel monkey, and rodents include mice and rats. Studies of circadian rhythm have occurred in hamsters. Beginning in the mid-2000s onwards, reports re-examining these effects have questioned the applicability of interspecies scaling models for MDMA, and have supported nonlinear pharmacology [78, 107, 108]. In general, doses in the range of 1 to 5 mg/kg in animals are relevant to human research and are described in more detail in Section Pharmacodynamics in Animals. Findings in doses above this that show a toxic effect are described when relevant in Section 4.4 Toxicology in Animals and Epidemiological Settings. Evidence exists for intentional human use of MDMA, known as Ecstasy among other names, as early as the late 1960s [57], and there are records of a police seizure of MDMA in the early 1970s [109]. MDMA was administered to thousands of people prior to scheduling and many continue to use Ecstasy around the world in various non-medical settings [1-5]. In this IB, Ecstasy (or other common names) refers to material assumed to be MDMA used in naturalistic settings (see epidemiology sections), however when used in these uncontrolled settings the drug may not contain only or any MDMA. One of the problems in assessing the effects of Ecstasy in users is determining the purity and identity of the substance. It may contain other substances along with Page 13 of 143

14 or instead of MDMA, and when present, the amount of MDMA can vary widely [ ]. The majority of studies rely on self-reported use and do not attempt to confirm that material used is MDMA. Synthesis of MDMA is relatively simple, and is often produced illegally in laboratories with no quality control, these synthesized tablets also may be cut or mixed with other psychoactive substances. Substances found mixed with MDMA have included amphetamine methamphetamine, dextromethorphan, paramethoxymethamphetamine (PMMA), paramethoxyamphetamine (PMA), cathinones, ketamine, caffeine, and ephedrine. Retrospective studies in Ecstasy users are described in Section 4.3 Physiological Effects in Epidemiological Settings and case reports of morbidity and mortality in Ecstasy users are included in Section 4.5 Serious Reports, Mortality, and Morbidity in Animals and Epidemiological Settings to provide the context of potential safety information of a related compound to MDMA which has extensive use outside of a research setting. 4.1 Nonclinical Pharmacology MDMA possesses a complex pharmacological profile that is dominated by its effects as a monoamine releaser and reuptake inhibitor. Its prominent effects on serotonin differentiate it from amphetamine and methamphetamine, which primarily act on dopamine and norepinephrine [21, 60]. In the following sections, the pharmacology of MDMA is presented based on nonclinical animal studies and epidemiological studies. 4.2 Pharmacology in Animals Pharmacokinetics in Animals MDMA is metabolized via two hepatic pathways. In the major pathway in rats, MDMA is O- demethylenated by cytochrome P450 CYP2D1 and 3A2 to form HHMA, which is O-methylated to generate HMMA by catechol-o-methyltransferase (COMT). In the minor pathway in rats, MDMA is N-demethylated by CYP1A2 and 2D1 to form MDA, which is an active metabolite. MDA is O-demethylenated by the same enzymes as MDMA, with subsequent metabolism by COMT. Metabolites of MDMA are excreted in urine as glucuronide and sulfate conjugates. MDMA and metabolites have shorter half-lives in rats than humans at comparable doses based on plasma C max values. Rats tend to form more MDA and glucuronide-conjugated metabolites than humans [113]. As MDMA dose increases above 2.5 mg/kg s.c. or i.p. in rats, a larger percentage of the administered dose is shunted to the N-demethylation pathway, resulting in greatly enhanced formation of MDA [114]. Comparison of metabolic pathways between rats and mice given 10 mg/kg intraperitoneal (i.p.) MDMA indicate that 49.1% of MDMA is metabolized through the HMMA pathway in mice versus 72% in rats, and 18.3% of MDMA is metabolized through the MDA pathway in mice versus 28% in rats based on AUC ratios to MDMA. MDMA at 10 mg/kg was also found to be eliminated more rapidly in mice (0.4 hours, i.p.) than rats at (1.1 hours, subcutaneous (s.c.)) [78, 115]. To address questions of the applicability of interspecies scaling models and nonlinear pharmacology of MDMA, a study examining MDMA and metabolites in rats given 2.5, 5, and 10 mg/kg s.c. found that MDMA metabolism is nonlinear in rats, with 2.5 mg/kg producing plasma C max levels approximating those seen in humans receiving between 75 and 100 mg [14, 114, 116]. Injections of 2 mg/kg s.c. or i.p. in rats were found to be similar to oral administration of 100 mg MDMA in humans based on plasma MDMA and metabolite concentrations [78]. Based on plasma values, a dose of 3 mg/kg i.p. MDMA administered in mice was comparable to a single oral dose of 100 mg in humans [94]. Studies in rats and mice provide compelling evidence of nonlinear pharmacokinetics, likely due to saturation of metabolic enzymes, determined by greater Page 14 of 143

15 than expected AUC values for MDMA and MDA after subsequent MDMA doses, while AUCs for HHMA and HMMA remained lower than expected [114, 115]. Single dose pharmacokinetics of oral 7.4 mg/kg MDMA in squirrel monkeys shows two to threefold higher plasma MDMA concentrations than humans receiving an oral dose of 100 mg, although allometric interspecies scaling predicts an equivalent dose [107]. A study directly comparing MDMA pharmacokinetics in humans and monkeys found that the two species metabolized MDMA in a similar but not identical manner - MDMA half-life in monkeys was less than half the duration seen in humans (1.1 hours at a dose of 2.8 mg/kg in squirrel monkeys versus 8.4 hours after 1.5 mg/kg in humans). Both monkeys and humans exhibit nonlinear pharmacokinetics [14, 118, 119], and it appears they exhibit similar plasma MDMA levels after receiving the same dose of MDMA [119, 120]. These pharmacokinetic findings suggest that nearly all toxicological and behavioral preclinical studies of MDMA use overestimated doses that exceed human-equivalent doses by 2.7 to 10.7 times, depending on route of administration, due to both simple dose conversion and allometric scaling. As a consequence, it is difficult to interpret the relevance of findings in preclinical studies employing these dosing regimes. Table 1: Pharmacokinetic Constants for Plasma MDMA After Various Routes of Administration to Humans or Animals Cmax (ng/ml) AUC (h ng/ml) Tmax (h) t1/2 (h) References Rat A 2 mg/kg i.p. 210± ± ± ±0.16 [78] 2 mg/kg s.c. 196±50 304± ± ±0.14 [78] 2 mg/kg p.o. 46±15 61± ± ±0.11 [78] 2.5 mg/kg s.c ± ± ± ±0.9 [114] 5 mg/kg s.c ± ± ± ±0.1 [114] 10 mg/kg s.c ± ± ±0.4 2±0.6 [114] Mouse B 3 mg/kg i.p. C [94] 10 mg/kg i.p. 1109± ± [115] 20 mg/kg i.p. 2152± ± [115] Squirrel Monkey 1.4 mg/kg p.o ± ± ± ±0.9 [121] 2.8 mg/kg p.o ± ± ± ±0.8 [121] 5.7 mg/kg p.o ± ± ± ±0.7 [121] 10 mg/kg p.o ± ,839.2± ± ±1.5 [121] 7.4 mg/kg s.c. 1227± ± ±0.9 [107] 7.4 mg/kg p.o. 773± ± ±0.5 [107] Human 1.0 mg/kg p.o. 147± ± ± ±0.6 [122] 1.6 mg/kg p.o. 292± ± ± ±2.1 [116] 1.6 mg/kg p.o ± ± ± ±1.6 [119] 2.0 mg/kg p.o [14] A Male Sprague-Dawley rats B Male FVB mice C Fantegrossi et al. reported mean pharmacokinetic parameters of R(-)-MDMA and S(+)-MDMA after administering racemic MDMA. In this table, plasma racemic C max values estimated by taking sum of R(-) and S(+), while T max and t 1/2 presented as an average of the enantiomers values Pharmacodynamics in Animals Most effects of MDMA likely arise directly from monoamine reuptake inhibition and release, and indirectly from activation of downstream monoamine receptors and subsequent secretion of Page 15 of 143

16 neuromodulators oxytocin and AVP. MDMA binds primarily to membrane-bound monoamine transporters, which remove monoaminergic neurotransmitters from the space between neurons, known as the synaptic cleft. MDMA appears to alter the conformation of the transporters, enabling monoamines to diffuse out of the neuron rather than being actively transported into the presynaptic neuron [60, 123, 124]. MDMA prevents the reuptake of serotonin, and to a lesser extent, norepinephrine and dopamine, and facilitates release of these neurotransmitters [60, ]. The selectivity of MDMA for specific monoaminergic neurotransmitters is speciesdependent, and cannot solely be attributed to differences in binding affinity for specific reuptake transporters observed in vitro, as described below. In in vitro studies, MDMA was also found to compete with monoamines for sites on the vesicular monoamine transporter-2 (VMAT2), suggesting MDMA also promotes active release of monoamines from vesicular stores, in addition to inhibiting reuptake [ ]. MDMA can inhibit monoamine oxidase A (MAO-A) in vitro at high concentrations, which preferentially degrades serotonin, and leads to accumulation of extracellular serotonin in the synaptic cleft [131, 132]. Inhibition of MAO-A may have played a role in fatalities and medical emergencies seen after combining Ecstasy with MAO inhibitors in epidemiological settings [133, 134]. Spurred on by prior reports hypothesizing that apparent greater serotonergic toxicity of MDMA in primates, as compared to rodents, could be attributed to greater SERT affinity [135], researchers specifically examined affinity in cells transfected to express human monoamine transporters [127, 136]. These studies found that even though binding affinity of MDMA for the human norepinephrine transporter (NET) exceeded the affinity for SERT and dopamine transporters (DAT), serotonin was preferentially released over norepinephrine and dopamine [127], which may account for primarily serotonergic effects of MDMA. On the other hand, in rodents MDMA affinities for transporters are ordered as SERT>NET>DAT [137]. MDMA does not have as strong an affinity for the DAT as methamphetamine [21]. The ability of MDMA to stimulate release of pre-synaptic serotonin, norepinephrine, and dopamine in multiple brain regions and inhibit reuptake has been well documented [138]. In vivo microdialysis and voltammetry results show significant enhancement of serotonin, and to a lesser extent dopamine following MDMA administration, a response attenuated by various transporter inhibitors. MDMA-stimulated serotonin and dopamine release has been measured in the striatum, nucleus accumbens, PFC, and the hippocampus of freely moving rats [ ]. In addition, enhancement of Ach release has been demonstrated in the PFC, striatum, and hippocampus by both a dopaminergic and serotonergic dependent mechanism [143, 144]. The subjective and physiological effects of MDMA are produced by the dynamic interaction of these transmitter systems on numerous brain networks that modulate learning and memory, emotion, reward, attention, sympathetic/parasympathetic activity, and neuroplasticity. In addition to carrier-mediated monoamine release, MDMA has affinity in vitro for specific serotonin, norepinephrine, Ach, and histamine receptors, although the concentrations tested may not translate to standard human MDMA doses [24, ]. An in vitro binding study comparing MDMA with a number of drugs that include cathinone derivatives suggests that contrary to an earlier report of low affinity for 5HT 2A serotonin receptors, MDMA may have significant effects at the receptor [25]. MDMA likely modulates 5HT 1A serotonin receptors indirectly through serotonin release, though it is possible that MDMA may also act as a partial 5HT 1A agonist in some brain areas [148]. Findings from other studies suggest that MDMA shares qualities with 5HT 1A agonists. Early studies in rats suggest that pharmacological activation of 5HT 1A receptors reduce anxiety and aggression [149, 150], and some drug discrimination studies suggest that the 5HT 1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) partially or fully substitutes for MDMA [ ]. In addition to its primary effects, both enantiomers of MDMA enhance Ach release in the PFC [144, 154] and promote changes in GABA-ergic systems Page 16 of 143

17 that correlate with sociability [155]. At least some direct or indirect effects of MDMA on serotonin receptors may alter GABA uptake in the ventral tegmental area of rats [156]. An in vitro study found that S-MDMA showed signs of competitive interaction with the alpha-4 beta-2 nicotinic receptor which are implicated in learning [157], while R-MDMA did not produce this effect [102]. Infusion of serotonin in the rat brain stimulates secretion of oxytocin into peripheral blood via activation of 5HT 1A, 5HT 2C, and 5HT 4 receptor subtypes, as well as AVP secretion via activation of 5HT 2C, 5HT 4, and 5HT 7 receptor subtypes [158]. MDMA was shown to increase oxytocin and AVP secretion in rats [159] through a 5HT 1A mechanism [160]. Administering a 5HT 1A antagonist attenuates the prosocial behavior of rats, measured by preference to lie adjacent to each other, possibly because it prevents elevation in oxytocin [160, 161]. MDMA also promotes norepinephrine release through reuptake inhibition, which is an additional pathway that can contribute to oxytocin secretion and may control emotion regulation. Both oxytocin and AVP are implicated in the widespread regulation of behavioral aspects of mood and also act on different target organs to modulate physiological functions in the periphery [162]. Taken together, MDMA has been shown to have a diverse array of pharmacodynamic effects in animals, with findings of interest presented below by topic Stable Effects on Gene Expression in Animals Epigenetic modifications, including deoxyribonucleic acid (DNA) methylation, demethylation, and histone acetylation, are thought to be involved in dynamic regulation of memory reconsolidation in the adult nervous system and play a role in memory formation [163]. Early childhood adversity and trauma is associated with transcriptional silencing of the brain-derived neurotrophic factor (BDNF) gene through DNA methylation, which can either be a risk factor in development of PTSD or a result of having PTSD in adulthood [164]. In a 2015 report, MDMA showed DNA hypermethylation and hypomethylation activity in cardiac tissue by microarray analysis in mice [165], and this activity may extend the CNS. Epigenetic effects on BDNF and other gene expression is a hypothesized mechanism by which MDMA in combination with training in animal studies modeling anxiety disorders, or psychotherapy in humans, exerts its therapeutic effects. A number of research teams have studied the effects of MDMA on gene expression in rodents [ ]. However, many of these reports used 10 to 20 mg/kg MDMA, a dose range that is 5 to 10.7 times greater than the 1.5 to 2 mg/kg doses employed in human trials, making it less likely that these changes can be generalized to humans given lower doses. However, even at these doses toxicity was not observed, and a self-administration study at clinically relevant doses reproduced findings of elevation of genes such as serum/glucocorticoid kinase 1 and 3 (Sgk1, Sgk3), which regulate glutamatergic signaling and are associated with neuroplasticity and learning, as well as processes involved in memory consolidation in serotonergic neurons [170]. These studies also report an increase in expression of genes that regulate the GABA transporter [166], which is expressed in GABA-ergic neurons indirectly regulated by glutamatergic afferent neurons. Serotonin-transporter knockout mice did not display some of these changes in gene transcription, suggesting that serotonin release is required for this activity [166]. In the acute period 24 to 48 hours after MDMA exposure, a study in rats found 33 to 70% upregulation of BDNF messenger ribonucleic acid (mrna) transcripts in the frontal cortex, with a time-dependent decrease, up to 73%, of BDNF transcripts in the hippocampus [171]. The frontal cortex and hippocampus are both regions known to play a causal role in memory retrieval and reconsolidation in animals and humans [172], mediated in part through GABA-ergic signaling [173], suggesting that these transcriptional changes may be functionally related. Page 17 of 143